Metastasis, a process where cancer cells migrate to distant organs from the primary tumor site, is the key biological process responsible for 90% of all cancer related deaths. Metastatic dissemination of cancer cells is a multi-step biological process initiated by tumor angiogenesis and invasion of the cancer cells through their surrounding stroma toward the blood vessels.
Tumor stroma is a structurally complex microenvironment hosting several cell types including endothelial cells (ECs), fibroblasts (FBs) and macrophages, packed in extracellular matrix (ECM), along with a dense network of capillaries. In this respect, the reciprocal interactions of the cancer cells with the surrounding microenvironment significantly influence their malignancy. Therefore, investigation of metastatic behavior of cancer cells in response to various microenvironmental stimuli is the key factor to identify efficient therapeutic strategies.
In the past few years, significant efforts have been devoted toward studying the mechanism of cancer metastasis, using in vivo and in vitro models. Genetically modified animal models have been crucially important to define the molecular basis of disease progression. However, using these models, there are certain difficulties to independently study the effects of various microenvironmental cues (i.e., cell-cell communication, mechanical properties of the matrix) on cancer cells metastasis. Furthermore, extensive testing of therapeutic compounds using in vivo models is a costly process.
Alternatively, in vitro assays have been widely used to study cancer cells behaviors (i.e. migration) within well-controlled experimental conditions. In vitro cell migration studies have been typically performed using 2D rigid substrates, Boyden chambers and transwell-based assays. Although these assays have facilitated high throughput and economically efficient experimental analysis, they do not fully recapitulate the complexities of the native 3D tumor microenvironment.
On the other hand, 3D macroscale ECM hydrogels and scaffolds (i.e. collagen) have shown a great promise for conducting fundamental research in cancer biology. Interestingly, such studies have demonstrated similar drug resistance profiles to those demonstrated by in vivo models. The limiting aspects of 3D macroscale hydrogel models are the lack of precise control over cellular distribution, lack of vascularity and difficulties in establishing stable chemical gradients throughout the 3D matrix for potential drug screening applications.
Recent advances in micro- and nanoscale (i.e. micropatterning, microfluidics) technologies have enabled the development of innovative platforms to study cancer cell migration within well-defined 3D microenvironments. Despite significant progress, most of the previously developed platforms have relied on simplified models to study the effects of a limited number of microenvironmental cues (i.e., matrix elasticity) on cancer metastasis. For instance, only a few studies have incorporated stromal cells (i.e. macrophages, FBs) within their model to recapitulate a physiologically relevant tumor microenvironment.
The breast tumor microenvironment is a complex milieu consisting of numerous cells types including fibroblasts and immune cells, packed in extracellular matrix (ECM), along with a dense network of capillaries. While previous research has demonstrated that the crosstalk between the cancer cells and their surrounding microenvironment significantly influences their metastatic potential, the success of therapeutic approaches to suppress breast tumor progression has been insufficient. A critical challenge in efficient translation of therapeutic strategies to clinical practice is the lack of physiologically relevant tumor models to study metastatic dispersion of cancer cells in response to microenvironmental stimuli within well-controlled experimental conditions.
Accordingly, due to the complexities associated with the native tumor stroma, there is an unmet need to develop physiologically relevant model in vitro microenvironments, in order to explore the metastatic behavior of cancer cells in response to a wide range of biophysical and biochemical stimuli.